Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
  • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
  • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
  • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

• the present invention relates to oral compositions for the delivery of pharmacologically active agents, to methods of enhancing the bioavailability of orally administered pharmacologically active agents, and to methods of treating and/or preventing disease in mammals, particularly humans, by orally administering a pharmacologically active agent in accordance with the invention.
• Oral delivery of pharmacologically active agents is generally the delivery route of choice since it is convenient, relatively easy and generally painless, resulting in greater patient compliance relative to other modes of delivery.
• biological, chemical and physical barriers such as varying pH in the gastrointestinal tract, powerful digestive enzymes, and active agent impermeable gastrointestinal membranes, makes oral delivery of some pharmacologically active agents to mammals problematic, e.g.
• calcitonins which are long-chain polypeptide hormones secreted by the parafollicular cells of the thyroid gland in mammals and by the ultimobranchial gland of birds and fish, has proven difficult due, at least in part, to the insufficient stability of calcitonin in the gastrointestinal tract as well as the inability of calcitonin to be readily transported through the intestinal walls into the blood stream.
• U.S. Patent Nos. 5,773,647 and 5,866,536 describe compositions for the oral delivery of active agents, such as heparin and calcitonin, with modified amino acids, such as, N-(5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC), N-(10-[2-hydroxybenzoyl]aminodecanoic acid (SNAD), and N-(8-[2-hydroxybenzoyl]amino)caprylic acid (SNAC)
• WO 00/059863 discloses the disodium salts of formula I wherein
• compositions which provide still greater oral bioavailability of pharmacologically active agents, e.g. peptides such as calcitonin.
• the present disclosure is directed to pharmaceutical compositions which, quite surprisingly, greatly enhance the oral bioavailability of active agents, particularly peptides.
• the invention provides a solid oral pharmaceutical composition in the form of a tablet or caplet, comprising calcitonin, the delivery agent 5-CNAC and crospovidone as an excipient.
• the invention is directed to a method for enhancing the oral bioavailability of a calcitonin, said method comprising administering to a subject in need of said-calcitonin an effective amount of a pharmaceutical composition according to the instant invention.
• the invention is directed to a method of treatment of bone related diseases and calcium disorders comprising administering to a patient in need of such treatment a therapeutically effective amount of a composition according to the instant invention.
• the present invention provides the composition of the invention for use in a method of treatment of bone related diseases and calcium disorders.
• the pharmacologically active agents suitable for use in the instant invention are calcitonins.
• Calcitonins have varying pharmaceutical utility and are commonly employed in the treatment of e.g. Paget's disease, hypercalcemia and postmenopausal osteoporosis.
• Various calcitonins, including salmon, pig and eel calcitonin are commercially available and commonly employed for the treatment of e.g. Paget's disease, hypercalcemia of malignancy and osteoporosis.
• the calcitonin can be any calcitonin, including natural, synthetic or recombinant sources thereof, as well as calcitonin derivatives such as 1,7-Asu-eel calcitonin.
• the compositions can comprise a single calcitonin or any combination of two or more calcitonins.
• the preferred calcitonin is synthetic salmon calcitonin.
• the calcitonins are commercially available or may be synthesized by known methods.
• the amount of pharmacologically active agent is generally an amount effective to accomplish the intended purpose, e.g. a therapeutically effective amount. However, the amount can be less than that amount when a plurality of the compositions are to be administered, i.e., the total effective amount can be administered in cumulative dosage units. The amount of active agent can also be more than the effective amount when the composition provides sustained release of the pharmacologically active agent. The total amount of active agent to be used can be determined by methods known to those skilled in the art. However, because the compositions may deliver the active agent more efficiently than prior compositions, less amounts of active agent than those used in prior dosage unit forms or delivery systems can be administered to a subject while still achieving the same blood levels and/or therapeutic effects.
• the appropriate dosage will, of course, vary depending upon, for example, the host and the nature and severity of the condition being treated. However, in general, satisfactory results will be obtained systemically at daily dosages of from about 0.5 ⁇ g/kg to about 10 ⁇ g/kg animal body weight, preferably 1 ⁇ g/kg to about 6 ⁇ g/kg body weight.
• the pharmacologically active agent generally comprises from 0.05 to 70 percent by weight relative to the total weight of the overall pharmaceutical composition, preferably an amount of from 0.01 to 50 percent by weight, more preferably 0.3 to 30 percent by weight relative to the total weight of the overall pharmaceutical composition.
• the crospovidone can be any crospovidone.
• Crospovidone is a synthetic crosslinked homopolymer of N-vinyl-2-pyrrolidone, also called 1-ethenyl-2-pyrrolidinone, having a molecular weight of 1,000,000 or more.
• Commercially available crospovidones include Polyplasdone XL, Polyplasdone XL-10, Polyplasdone INF-10 available from ISP, Kollidon CL, available from BASF Corporation.
• the preferred crospovidone is Polyplasdone XL.
• the crospovidones are commercially available. Alternatively, they may be synthesized by known processes.
• the crospovidone is generally present in the compositions in an amount of from 0.5 to 50 percent by weight relative to the total weight of the overall pharmaceutical composition, preferably an amount of from 2 to 25 percent, more preferably 5 to 20 percent by weight relative to the total weight of the pharmaceutical composition.
• the delivery agent useful in the present disclosure is N-(5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC), N-(10-[2-hydroxybenzoyl]amino)decanoic acid (SNAD), N-(8-[2-hydroxybenzoyl]amino)caprylic acid (SNAC)and their monosodium and disodium salts, ethanol solvates of their sodium salts and the monohydrates of their sodium salts and any combinations thereof.
• the most preferred delivery agent is the disodium salt of 5-CNAC and the monohydrate thereof.
• 5-CNAC as well as its disodium salts and alcohol solvates and hydrates thereof are described in WO 00/059863 , along with methods for preparing them.
• the disodium salt may be prepared from the ethanol solvate by evaporating or drying the ethanol solvate by methods known in the art to form the anhydrous disodium salt. Drying is generally carried out at a temperature of from about 80 to about 120°C, preferably from about 85 to about 90°C, and most preferably at about 85°C. The drying step is generally performed at a pressure of 26" Hg or greater.
• the anhydrous disodium salt generally contains less than about 5% by weight of ethanol and preferably less than about 2% by weight of ethanol, based on 100% total weight of anhydrous disodium salt.
• the disodium salt of the delivery agent can also be prepared by making a slurry of the delivery agent in water and adding two molar equivalents of aqueous sodium hydroxide, sodium alkoxide or the like.
• Suitable sodium alkoxides include, but are not limited to, sodium methoxide, sodium ethoxide, and combinations thereof.
• a still further method of preparing the disodium salt is by reacting the delivery agent with one molar equivalent of sodium hydroxide to yield the disodium salt.
• the disodium salt can be isolated as a solid by concentrating the solution containing the disodium salt to a thick paste by vacuum distillation. This paste may be dried in a vacuum oven to obtain the disodium salt of the delivery agent as a solid. The solid can also be isolated by spray drying an aqueous solution of the disodium salt.
• the delivery agents may be prepared by methods known in the art, e.g., as mentioned above, by methods described in US Patent Nos. 5,773,647 and 5,866,536 .
• the ethanol solvates include, but are not limited to, a molecular or ionic complex of molecules or ions of ethanol solvent with molecules or ions of the disodium salt of the delivery agent.
• the ethanol solvate contains about one ethanol molecule or ion for every molecule of disodium salt of the delivery agent.
• the ethanol solvate of the disodium salt of the delivery agent can be prepared by dissolving the delivery agent in ethanol.
• each gram of delivery agent is dissolved in from about 1 to about 50mL of ethanol and generally, from about 2 to about 10mL of ethanol.
• the delivery agent/ethanol solution is then reacted with a molar excess of a sodium containing salt, such as a monosodium containing salt, relative to delivery agent, i.e. for every mole of delivery agent there is more than one mole of sodium cations, yielding the ethanol solvate.
• a sodium containing salt such as a monosodium containing salt
• Suitable monosodium salts include, but are not limited to, sodium hydroxide; sodium alkoxides, such as sodium methoxide and sodium ethoxide; and any combination of the foregoing.
• at least about two molar equivalents of the monosodium containing salt are added to the ethanol solution, i.e. for every mole of delivery agent there is at least about two moles of sodium cations.
• the reaction is performed at or below the reflux temperature of the mixture, such as at ambient temperature.
• the ethanol solvate is then recovered by methods known is the art, such as, concentration of the resulting slurry at atmospheric distillation, cooling the concentrated slurry and filtering the solid.
• the recovered solid can then be vacuum dried to obtain the ethanol solvate.
• the hydrates of the disodium salts of the delivery agents may be prepared by drying the ethanol solvate to from an anhydrous disodium salt, as described above, and hydrating the anhydrous disodium salt.
• the monohydrate of the disodium salt is formed.
• the hydrate forms upon exposure to atmospheric moisture.
• the hydrating step is performed at from about ambient temperature to about 50°C, preferably ambient temperature to about 30°C and in an environment having at least 50% relative humidity.
• the anhydrous disodium salt may be hydrated with steam.
• compositions of the present disclosure typically contain a delivery effective amount of one or more of the delivery agents, i.e. an amount sufficient to deliver the active agent for the desired effect.
• the delivery agent is present in an amount of 2.5% to 99.4% by weight, more preferably 25% to 50% by weight.
• compositions of the present invention is provided as a tablet or caplet, all of which can be prepared by methods well known in the art.
• compositions may additionally comprise additives in amounts customarily employed including, but not limited to, a pH adjuster, a preservative, a flavorant, a taste-masking agent, a fragrance, a humectant, a tonicifier, a colorant, a surfactant, a plasticizer, a lubricant such as magnesium stearate, a flow aid, a compression aid, a solubilizer, an excipient, a diluent such as microcrystalline cellulose, e.g. Avicel PH 102 supplied by FMC corporation, or any combination thereof.
• additives may include phosphate buffer salts, citric acid, glycols, and other dispersing agents.
• composition may also include one or more enzyme inhibitors, such as actinonin or epiactinonin and derivatives thereof; aprotinin,Trasylol and Bowman-Birk inhibitor.
• enzyme inhibitors such as actinonin or epiactinonin and derivatives thereof; aprotinin,Trasylol and Bowman-Birk inhibitor.
• a transport inhibitor i.e. a p-glycoprotein such as Ketoprofin, may be present in the compositions of the present invention.
• the solid pharmaceutical compositions of the instant invention include a diluent, such as Avicel, and a lubricant, such as magnesium stearate.
• a diluent such as Avicel
• a lubricant such as magnesium stearate
• the solid pharmaceutical compositions of the instant invention can be prepared by conventional methods e.g. by blending a mixture of the active agent, the delivery agent, the crospovidone and other ingredients, kneading, and molding followed by further tableting or compression-molding to give tablets.
• a solid dispersion may be formed by known methods followed by further processing to form a tablet.
• the ingredients in the pharmaceutical compositions of the instant invention are homogeneously or uniformly mixed throughout the solid dosage form.
• compositions of the present invention may be administered to deliver an active agent to any animal in need thereof, including, but not limited to, mammals, such as rodents, cows, pigs, dogs, cats, and primates, particularly humans.
• mammals such as rodents, cows, pigs, dogs, cats, and primates, particularly humans.
• Tablets were prepared in accordance with the present invention (EXAMPLE A) as well as COMPARATIVE EXAMPLES B AND C which utilize Ac-Di-Sol in place of the crospovidone (Ac-Di-Sol is cross-linked carboxymethylcellulose sodium) and COMPARATIVE EXAMPLE D, which is a colyophilized capsule containing 5-CNAC and salmon calcitonin.
• the tablets are prepared as follows:
• 0.502 of salmon calcitonin, pre-screened through a 40 mesh screen, 120 g of 5-CNAC disodium salt, pre-screened through a 35 mesh screen, and 20 g of Polyplasdone XL (crospovidone, NF) is combined in a 500 mL jar and is mixed using a Turbula mixer for 2 minutes at a speed of 46 RPM.
• An additional 125.4 g of 5-CNAC disodium salt, pre-screened through a 35 mesh screen, and 32.5 g of Avicel PH 102 is added to the jar and is mixed for a period of 8 minutes at a speed of 46 RPM.
• a further 32.5 g of Avicel is added to the jar and is mixed for 5 minutes at a speed of 46 RPM.
• magnesium stearate 4.0 g is screened into the jar using a 35 mesh screen and is blended for 1 minute at a speed of 46 RPM. The final blend is compressed into tablets using a Manesty B3B tablet press. The tablet weight is approximately 400 mg.
• 0.1224 of salmon calcitonin, pre-screened through a 40 mesh screen, 30 g of 5-CNAC disodium salt, pre-screened through a 35 mesh screen, and 4 g of Ac-Di-Sol are placed in a 500 mL Pyrex ® jar and are mixed using a Turbula mixer for 2 minutes at a speed of 46 RPM.
• An additional 31.35 g of 5-CNAC disodium salt, pre-screened through a 35 mesh screen, and 15 g of Avicel PH 102 are added to the jar and are mixed for a period of 8 minutes at a speed of 46 RPM.
• 2 g of CabOSil and 16.15 g of Avicel are combined and are screened through an 18 mesh screen.
• the CabOSil/Avicel mixture is added to the jar and is mixed for 5 minutes at a speed of 46 RPM.
• 1.5 g of magnesium stearate is screened into the jar using a 35 mesh screen and is blended for 2 minutes at a speed of 46 RPM.
• the final blend is compressed into tablets using a Manesty B3B tablet press.
• the tablet weights are approximately 400 mg.
• a phosphate buffer solution is prepared by adding 13.8 g of monosodium phosphate monohydrate, USP to 900 g of Water For Injection and adjusting to a pH of 4.0 utilizing a 1.0 N phosphoric acid solution.
• the phosphoric acid solution is prepared by adding 0.96 g of phosphoric acid, NF, to 25 mL of Water for injection.
• the final weight of the phosphate buffer solution is adjusted to 1007 g (density 1.007) using Water for Injection and is stirred for 5 minutes.
• a buffered salmon calcitonin solution is prepared by adding 1.6 g of salmon calcitonin to 660 g of the phosphate buffer solution. The final weight of the solution is adjusted to a final weight of 806.4 g (density 1.008) using the phosphate buffer solution and mixed for a minimum of 5 minutes at a speed of 250 RPM or less.
• 0.800 kg of the buffered salmon calcitonin solution is added dropwise to 20 kg of 5-CNAC solution with constant mixing at a speed of 250 RPM or less for a minimum of 5 minutes.
• colyophilized salmon calcitonin/5-CNAC is removed from the trays and stored in polyethylene and foils bags under refrigeration. Approximately 400 mg of colyophilized material is filled into capsules (size AA) for administration.
• Example 1 The tablets or capsules prepared in Example 1 are administered to Rhesus monkeys as follows: four to six monkeys in a group were each dosed with either one capsule or two tablets of Example 1 as follows:
• the Rhesus monkeys fast overnight prior to dosing and are restrained in chairs fully conscious, for the duration of the study period.
• the capsules or tablets are administered via a gavage tube followed by 10 mL of water.
• Plasma salmon calcitonin is determined by radioimmunoassay.
• the primate plasma salmon calcitonin (sCT) results from each group of monkeys is averaged and the maximum mean plasma calcitonin concentration and area under the curve (AUC) results are calculated and reported in Table 1.
• sCT primate plasma salmon calcitonin
• AUC area under the curve
• the salmon calcitonin Cmax and the salmon calcitonin AUC are much greater for the composition according to the present invention containing the crospovidone (Example A) versus the comparative compositions which do not contain crospovidone, resulting in greatly enhanced oral bioavailability of the formulations according to the instant invention.
• Tablets containing 0.065 mg, 0.400 mg, and 2.500 mg sCT are prepared according to Comparative Example C and Example A, respectively, with the sCT and Avicel adjusted in order to obtain the target strengths.
• the tablets are placed in a HDPE bottle with a desiccant, which is induction sealed and capped. Accelerated stability tests are conducted by placing the stability samples in environmental chambers at 25°C and 60% relative humidity. The samples are pulled at the specified time points, i.e. at 3, 4 and 6 weeks, and analyzed for sCT by HPLC. The results are shown in Table 2.
• Example C Comparison of Comparative Example C after 4 weeks (about a 10% decrease in sCT assay) with Example A according to the present invention after 6 weeks (about a 5% decrease in sCT assay), both at room temperature, demonstrates that the formulation according to the instant invention results in improved stability of the tablets prepared according to the instant invention.
• Tablet disintegration of the solid formulations was determined by preparing tablets as per Example 1 containing 60% 5-CNAC Disodium, 29% Avicel, 1% Magnesium Stearate, but excluding the sCT. Tablet disintegration was determined according to the USP Disintegration Test ⁇ 701> while tablet hardness was determined using a calibrated Vector/Schleuniger 6D Tablet Hardness Tester. The results are shown in Table 3.
• Samples for extreme stress stability testing are prepared by placing tablets (prepared analogously to those in Example 1, above, using the ratio of ingredients indicated in Table 4 in a capped amber bottle. Accelerated stability tests are conducted by placing the samples in a calibrated oven at 60°C. Samples are analysed for sCT initially and after either 3 or 4 days as specified by HPLC. The results are shown in Table 4. TABLE 4 Excipients 60°C Initial sCT Assay Stress sCT Assay % Change (0.4 mg sCT/200 mg 5-CNAC Disodium) Ac-Di-Sol, Cab-O-Sil, Avicel, Mg.
• Stearate (COMPARATIVE EXAMPLE C) 3 Days 94.0 % 12.3 % - 81.7 % 10% PolyplasdoneXL-10, Avicel, Mg. Stearate (EXAMPLE A) 4 Days 98.3 % 86.5 % -11.8 %
• compositions according to the instant invention have considerably improved oral bioavailability of calcitonin, relative to other oral formulations, good disintegration rates and excellent stability.

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